Prion diseases are infectious, conformational neurodegenerative disorders characterized by the structural modification of the prion protein, PrPC, into a pathological conformer, PrPSc. Currently there is no effective therapy for this group of diseases. The outbreak of bovine spongiform encephalopathy and the resulting emergence of a new human prion disease vCJD, highlight the public health threat from prion diseases. Although the original outbreak of vCJD is waning, there is the possibility of further outbreaks from current asymptomatic carriers of the disease. In the USA an ongoing threat from prion disease is from chronic wasting disease (CWD). High rates of infection among deer and elk populations have been report, with experimental data indicating that this disease is transmissible to primates. We reported on the first successful in vivo active and passive immunization approaches for prion diseases using wild-type animals. In addition, we have also developed an in vitro tissue culture model of prion disease, and showed that it is a valuable tool to screen for therapeutically active anti-PrP antibodies. Our preliminary results indicate that using our novel mucosal immunization approach we are able to completely prevent prion disease in mice with a high anti-PrP titer. We also have shown that anti-PrP antibodies that are active in our tissue culture model of prion infection, can significantly delay prion infection and reduce severity of disease. In our planned studies we will test this approach in wild-type mule deer to test the efficacy of this approach to prevent CWD. In the specific aims of this supplement we plan: 1) In collaboration with Dr. Edward Hoover, we will orally vaccinate a group of six mule deer with our Salmonella expressing cervid PrP. An additional group of 6 mule deer will be exposed to the vector Salmonella as a control. This will be done with a series of inoculations, during this time the anti-PrP response will be monitored. 2) The two mule deer populations will then be challenged with the oral CWD agent. The immune responses will be monitored with repeated bleedings and biopsies of the tonsils and rectal mucosa. After 18 months or when the animals develop CWD, the animals will be sacrificed and levels of PrPCWD determined. We will establish the effectiveness of the vaccine in preventing CWD replication. This will provide data on the utility of our vaccine in the target population, bringing such a vaccine closer to veterinary use. A vaccine could potentially retard or stop the CWD epidemic in the USA. PUBLIC HEALTH RELEVANCE: Currently prion diseases are without treatment and are universally fatal. The past outbreak of bovine spongiform encephalopathy with the resulting emergence of variant Creutzfeldt-Jakob disease, as well as the currently epidemic of chronic wasting disease among deer and elk in the USA, which has been shown to be transmissible to primates, all highlights the public health threat from this group of disorders. This competitive revision proposal aims to develop active vaccination in mule deer to prevent the spread of CWD in animals, reducing the possibility of CWD infecting humans.